This blog is devoted to the discussion of all aspects of synthetic organic chemistry and related sciences. Curly Arrow is run by a synthetic organic chemist based in Copenhagen, Denmark. Contributions from readers are always welcome and should be emailed to curlyarrow@gmail.com

Thursday, February 05, 2009

Say hello to diazidomethane. Is it time for a change of underwear yet? I work with azides on a daily basis and I even determine the melting point of my azides. My azides are nice a stable because they all adhere to the 6 heavy atoms (carbon or heavier) per azido-group rule of thumb. However, if you stray from the 6 heavy atom path you are looking for trouble and if you decide to do 1/2 a carbon per azide as we have in this case you will be looking for a new chemistry department.

In this really interesting paper from Alcon Research Ltd. they unintentionally made a fair bit of diazidomethane when performing the synthetic sequence shown in the scheme below. To remove residual dichloromethan after the first step the chemists at Alcon redissolved the crude product in DMF and concentrated it to dryness. To my (and theirs I'm sure) surprise this doesn't remove all dichloromethane despite a huge difference in boiling point. After performing the second step, they worked the reaction up and concentrated it on a rotary evaporator.

This is what they observed when they came back the next morning:

“... it was noted that about 30 mL of a twophase liquid had collected in the glass crosspiece at the bottom of the condenser assembly.”

When they attempted draining the stuff it decided to go nuts. All I’ll say is that nobody died but you’ll have to dig the paper out yourself if you want the full story.

Evans group published procedure for alpha-bromine displacement on their acylated auxiliary, using tetramethyl guanidinium azide in DCM - and no-one apparently had any mishap at Harvard. Some years later Hruby group at U of Arizona was using this published work as a precedent and they were doing it on a multigram scale, and since their substrates were more hindered they refluxed their experiments for a day or two. They had several nasty detonations, always on rotovap, before they figured what was going on.

We had a dude in Prague in student labs who came to his supervisor and complained that he was drying carbon tetrachloride with sodium metal but somehow this system was producing lots of black muck. The boss had just one look at the giant bubbling flask with lumps of sodium floating on top and zipping around - and he immediately evacuated the lab. (I don't know how they disposed this wonderful Na + CCl4 mix.)

When we wanted to introduce an azido group into nucleoosdes, LIN3 was proposed, but I could settle down to sodium azide.. and the rexn., was insitu and quantitative, which we reduced to amino....After reading this... I got back to my early memories of doing the rexns., thanx, for the info.

I have used CH2Cl2/water mix with phase transfer conditions and NaN3 on a number of occasions. In fact I would say that it is an excellent way of preparing sulfonylazides for diazo transfer.

I am not quite sure if I believe the Org. Proc. Paper... As I don't think they actually demonstrated that they had made diazidomethane. It seems that it was more of a postulate. It seems much more likely that they produced HN3 which is also quite explosive. If the entire rotovap exploded it would probably have been caused by a build up of HN3 in the system.. not the concentrated diazidomethane(whose boiling pt is almost certainly not lower than DCM.

the DCM reaction with azide is not very fast - in fact it usually happens at or above the DCM boiling point (>40C), over the course of several hours. I hope that the anonymous philistine will not have the joy of preparing diazidomethane himself, despite his insistence that DCM and azide combo is the greatest.

No need to produce sulfonylazides in biphasic conditions. There was a procedure in Tett. Lett. a couple years ago. It's quite simple. NaN3 in pyridine, add Tf2O, then add to amine. Works like a charm, no need to use buckets of NaN3 either.

An anonymous source emailed me the following comment:"Of course they thought of HN3...but the proton and carbon NMR of the residue showed diazidomethane. Nothing else shows those resonances. The "exploding rotovap effect" has plenty of precedent and diazidomethane is undoubtedly the culprit. The fact that Anonymous has escaped explosion so far doesn't mean he always will be so lucky, another point that was made in the Alcon paper. Most of the older accidents involved phase transfer conditions, including the reference by Huw Davies in Synth. Commun., for which he himself wrote a disclaimer found in a footnote of the Alcon paper." D!